Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur ...within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.
Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.
In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks.
The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.
ClinicalTrials.gov NCT01851733.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glioblastoma (GBM) is the most common malignant brain tumor. Despite multimodality treatment with surgical resection, radiation therapy, chemotherapy, and tumor treating fields, recurrence is ...universal, median observed survival is low at 8 months and 5-year overall survival is poor at 7%. Immunotherapy aims to generate a tumor-specific immune response to selectively eliminate tumor cells. In treatment of GBM, immunotherapy approaches including use of checkpoint inhibitors, chimeric antigen receptor (CAR) T-Cell therapy, vaccine-based approaches, viral vector therapies, and cytokine-based treatment has been studied. While there have been no major breakthroughs to date and broad implementation of immunotherapy for GBM remains elusive, multiple studies are underway. In this review, we discuss immunotherapy approaches to GBM with an emphasis on molecularly informed approaches.
There is a bewildering range of estimates for the number of arthropods on Earth. Several measures are based on extrapolation from species specialized to tropical rain forest, each using specific ...assumptions and justifications. These approaches have not provided any sound measure of uncertainty associated with richness estimates. We present two models that account for parameter uncertainty by replacing point estimates with probability distributions. The models predict medians of 3.7 million and 2.5 million tropical arthropod species globally, with 90% confidence intervals of 2.0, 7.4 million and 1.1, 5.4 million, respectively. Estimates of 30 million or greater are predicted to have <0.00001 probability. Sensitivity analyses identified uncertainty in the proportion of canopy arthropod species that are beetles as the most influential parameter, although uncertainties associated with three other parameters were also important. Using the median estimates suggests that in spite of 250 years of taxonomy and around 855,000 species of arthropods already described, approximately 70% await description.
We have conducted a survey of 341 interplanetary coronal mass ejections (ICMEs) using STEREO A/B data, analyzing their properties while extending a Level 3 product through 2016. Among the 192 ICMEs ...with distinguishable sheath region and magnetic obstacle, the magnetic field maxima in the two regions are comparable, and the dynamic pressure peaks mostly in the sheath. The north/south direction of the magnetic field does not present any clear relationship between the sheath region and the magnetic obstacle. About 71% of ICMEs are expanding at 1 au, and their expansion speed varies roughly linearly with their maximum speed except for ICMEs faster than 700 km s−1. The total pressure generally peaks near the middle of the well-defined magnetic cloud (MC) passage, while it often declines along with the non-MC ICME passage, consistent with our previous interpretation concerning the effects of sampling geometry on what is observed. The hourly average iron charge state reaches above 12+ ∼31% of the time for MCs, ∼16% of the time for non-MC ICMEs, and ∼1% of the time for non-ICME solar wind. In four ICMEs abrupt deviations of the magnetic field from the nominal field rotations occur in the magnetic obstacles, coincident with a brief drop or increase in field strength-features could be related to the interaction with dust. In comparison with the similar phases of solar cycle 23, the STEREO ICMEs in this cycle occur less often and are generally weaker and slower, although their field and pressure compressions weaken less than the background solar wind.
Purpose
Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A ...previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ.
Methods
This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety.
Results
From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1–12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase).
Conclusions
Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.
Current machine vision-based detection methods for metal surface roughness mainly use the grey values of images for statistical analysis but do not make full use of the colour information and ignore ...the subjective judgment of the human vision system. To address these problems, this paper proposes a method to measure surface roughness through the sharpness evaluation of colour images. Based on the difference in sharpness of virtual images of colour blocks that are formed on grinding surfaces with different roughness, an algorithm for evaluating the sharpness of colour images that is based on the difference of the RGB colour space was used to develop a correlation model between the sharpness and the surface roughness. The correlation model was analysed under two conditions: constant illumination and varying illumination. The effect of the surface textures of the grinding samples on the image sharpness was also considered, demonstrating the feasibility of the detection method. The results show that the sharpness is strongly correlated with the surface roughness; when the illumination and the surface texture have the same orientation, the sharpness clearly decreases with increasing surface roughness. Under varying illumination, this correlation between the sharpness and surface roughness was highly robust, and the sharpness of each virtual image increased linearly with the illumination. Relative to the detection method for surface roughness using gray level co-occurrence matrix or artificial neural network, the proposed method is convenient, highly accurate and has a wide measurement range.
Management of patients with glioblastoma (GBM) often includes radiation (RT) and temozolomide (TMZ). The association between severe treatment-related lymphopenia (TRL) after the standard ...chemoradiation and reduced survival has been reported in GBM patients with the median age of 57. Similar findings were described in patients with head and neck, non-small cell lung, and pancreatic cancers. This retrospective study is designed to evaluate whether elderly GBM patients (age ≥65) develop similar TRL after RT/TMZ and whether such TRL is associated with decreased survival. Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients (age ≥65) with newly diagnosed GBM undergoing RT/TMZ and associated with treatment outcomes. Seventy-two patients were eligible: median KPS 70, median age 71 years (range 65–86) with 56 % of patients >70 years, 53 % female, 31 % received RT ≤45 Gy. Baseline median TLC was 1100 cells/mm
3
which fell by 41 % to 650 cells/mm
3
2 months after initiating RT/TMZ (p < 0.0001). Patients with TLC <500 cells/mm
3
at 2 months had a shorter survival than those with higher TLCs with a median overall survival of 4.6 versus 11.6 months, respectively. Multivariate analysis revealed a significant association between TRL and survival (HR 2.76, 95 % CI 1.30–5.86, p = 0.008). Treatment-related lymphopenia is frequent, severe, and an independent predictor for survival in elderly patients with GBM. These findings add to the body of evidence that immunosuppression induced by chemoradiation is associated with inferior clinical outcomes. Prospective studies are needed to confirm these findings suggesting that immune preservation is important in this cancer.
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